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Microfilament Depletion and Circumvention of Multiple Drug Resistance by Sphinxolides¹

Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [X. Z., C. D. S.], and Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli "Federico II," Via D. Montesano, 49 80131 Napoli, Italy [L. M., A. Z.]

Sphinxolides, a newly described family of cytotoxins from the New Caledonian sponge Neosiphonia superstes, bear structural resemblance to scytophycins. We now demonstrate that the cytotoxicity of sphinxolides is associated with cell cycle arrest in G₂-M and induction of apoptosis. Like scytophycins and cytochalasins, sphinxolides caused rapid loss of microfilaments in cultured cells, without affecting microtubule organization. Microfilament reassembly was very slow after removal of the sphinxolide, consistent with the slow recovery of cellular proliferation. Sphinxolides potently inhibited actin polymerization in vitro and the microfilament-dependent ATPase activity of purified actomyosin, indicating a direct effect on actin. Importantly, sphinxolides were equally cytotoxic toward MCF-7 human breast carcinoma cells and a subline which overexpresses P-glycoprotein (MCF-7/ADR). Similarly, overexpression of the multidrug resistance-associated protein MRP by HL-60 cells did not confer resistance to the sphinxolides. These studies demonstrate that sphinxolides are potent new antimicrofilament compounds that circumvent multidrug resistance mediated by overexpression of either P-glycoprotein or MRP. Therefore, these agents may be useful in the treatment of drug-resistant tumors.

¹ Supported by Grant CA 64631 from the NIH (to C. D. S.).

² To whom requests for reprints should be addressed, at Department of Pharmacology, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111. Phone: (215) 728-3141; Fax: (215) 728-4333; E-mail: CD_Smith@FCCC.EDU.

Received 4/ 7/97. Accepted 7/ 7/97.

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